Breast cancer brain metastasis (BCBM) occurs in approximately 50% of late-stage Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer patients. BCBM may result in cognitive decline and cranial neuropathies and is associated with a median survival rate of nine months. Current therapies for BCBM, such as whole brain radiation therapy, can enhance cognitive impairment while targeted therapies and chemotherapy are ineffective. Despite the increased patient survival due to HER2 targeted therapies, patients often relapse due to brain metastases. Recently, our laboratory has discovered a role for Abelson (Abl) family of tyrosine kinases, ABL1 and ABL2, in breast cancer bone metastasis and lung cancer brain metastasis. Evaluation of 279 HER2+ breast cancer patients demonstrates a correlation between high expression of ABL1 and decreased distant metastasis free survival. My preliminary experiments have shown decreased brain colonization by HER2+ breast cancer cells when mice are treated with the allosteric Abl kinase inhibitor GNF5. I will evaluate the hypothesis that HER2 signals through Abl kinases to promote HER2+ breast cancer metastasis to the brain. This hypothesis will be tested in the following aims: (1) Identify the steps of the metastatic cascade that require Abl kinase signaling. (2) Elucidate the mechanism of Abl signaling in brain metastatic HER2+ breast cancer cells.